Our goal in this proposal is to assess the effect on HIV-1 replication in vitro, and on SHIV replication in vitro and in vivo, of combinations of agents proven by us in published studies to have broad and potent neutralizing activity against primary HIV-1 isolates, when used as single agents. The agents we plan to use are the human MAbs IgG1b12, 2G12 and 2F5 and the CD4-IgG2 molecule, which has many of the properties of a human MAb. We believe that broad, potent neutralization of primary isolates in vitro is of paramount importance in determining the suitability of MAbs for human clinical trials. Triple combinations of the above agents have outstanding HIV-1 neutralizing activity under cell culture conditions. We wish to test whether this in vitro effect correlates with in vivo reductions in viral load in SHIV-infected macaques, or predicts protection from SHIV infection. An emphasis of this proposal will be the use of HIV-1 and SHIV strains from genetic subtypes other than B, to facilitate the development of immunotherapy for the developing worlds. All four of the above agents have proven capacities to neutralize primary isolates from multiple HIV-1 genetic subtypes, including African and Asian strains. The information accruing from the proposed studies might assist in the identification of suitable immunotherapeutic strategies for the treatment of HIV-1 infection, or the prevention of HIV-1 transmission from infected mothers to their children, as well as providing information on the effects of neutralizing antibodies on the dynamics of HIV-1 production and clearance in vivo. FUNDING NIH (HL-97-002) PUBLICATIONS Trkola, A., T. Ketas, V.N. KewalRamani, F. Endorf, J.M. Binley, H. Katinger, J. Robinson, D.R. Littman and J.P. Moore. Neutralization sensitivity of human immunodeficiency virus type 1 primary isolates to antibodies and CD4-based reagents is independent of co-receptor usage. Journal of Virology, 72:1876-1885, 1998. Montefiori, D.C., R.G. Collman, T.R. Fouts, J.Y. Zhou, M. Bilska, J.A. Hoxie, J.P. Moore and D.P. Bolognesi. Evidence that antibody-mediated neutralization of human immunodeficiency virus type 1 by sera from infected individuals is independent of coreceptor usage. Journal of Virology, 72:1886-1893, 1998. Fouts, T.R., A. Trkola, M.S. Fung and J.P. Moore. Interactions of polyclonal and monoclonal anti-glycoprotein 120 antibodies with oligomeric glycoprotein 120-glyoprotein 41 complexes of a primary HIV type 1 isolate Relationship to neutralization. AIDS Research and Human Retroviruses, 14:591-598, 1998. Sullivan, N., Y. Sun, Q. Sattentau, M. Thali, D. Wu, G. Denisova, J. Gershoni, J. Robinson, J.P. Moore and J. Sodroski. CD4-induced conformational changes in the human immunodeficiency virus type 1 gp120 glycoprotein Consequences for virus entry and neutralization. Journal of Virology, 72:4694-4703, 1998. Burton, D.R. and J.P. Moore. Why do we not have an HIV vaccine and how can we make one? Nature Medicine, 4:495-498, 1998.